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Research Interests:
Molecular mechanisms of neurodegeneration. Oxidative stress, Cell signaling, Autophagy
Dr. Chu's laboratory investigates basic mechanisms of neuronal injury relevant to Parkinson's disease and other age-related neurodegenerative diseases. In particular, we focus upon oxidative regulation of neurotrophic and neurotoxic cell signaling pathways. A major focus is delineating factors that impair the normal, adaptive responses of neurons to oxidative and environmental toxins
We have discovered striking alterations in subcellular localization and function of extracellular signal regulated protein kinase (ERK) and cAMP response element binding protein (CREB) pathways in our cell culture models of Parkinsonian injury. Moreover, several of these changes are also observed in Parkinson's disease patient brains. We are currently testing the hypothesis that oxidative diversion of these signaling pathways results in loss of neuroprotective transcription factor function and gain of toxic cytoplasmic functions. Current efforts in the laboratory are directed at understanding the downstream consequences of altered kinase regulation and trafficking, including effects upon neurite injury and intracellular degradation. We are also investigating the function and role of PINK1, a novel mitochondrial kinase linked to autosomal recessive Parkinson's disease.
A second area of emphasis involves autophagy and the regulation of mitochondrial turnover. Oxidative mitochondrial injury has been implicated in human Parkinson's disease tissues as well as in animal models of Parkinson's disease, including our work in the mouse 6-hydroxydopamine and MPTP models. Using pharmacologic and siRNA tools, we have found that the signaling regulation of autophagy in the context of targeted mitochondrial injury is distinct from that of nonselective starvation-induced autophagy. Although autophagy is a compensatory response to starvation, it may also play a role in type II programmed cell death.
Experimental manipulation of oxidative catecholamines, reactive oxygen species and signaling proteins using phamacologic and molecular techniques in culture is complemented by biochemical and immunomicroscopic analysis of Parkinsonian animal models and diseased human brain tissues.
Techniques: Protein biochemistry, cell transfections, proteomic phosphoprotein profiling, quantitative RT-PCR, immunochemistry, multi-label confocal microscopy, EM, stereotactic brain injections, RNA interference (siRNA). For more information, see http://www.gradbiomed.pitt.edu/rotView.asp?pid=183 and http://www.gradbiomed.pitt.edu/rotView.asp?pid=185.
Educational initiatives:
Dr. Chu is committed to career development of pre-doctoral, post-doctoral and physician-scientist trainees. She is organizing and co-chairing the 2006 ASIP/FASEB Mentoring Luncheon on "Opening Doors: Networking and Professional Visibility" in San Francisco. She also leads the module on "Tissue injury, Cell Death & Disease" for the ASIP/FASEB Concepts in Pathobiology course.
Dr. Chu directs a Professional Development course designed to introduce MD/PhD students to writing and reviewing funding proposals and the importance of professional service.
For information on programs designed to transition physician scientist trainees into academic faculty professorships, please see the Pathologist Investigator Residency Training Program website http://www.pathology.pitt.edu/PIRT. This combined Residency-Post-doctoral Research Fellowship or combined Residency-PhD program is designed to develop Academic Pathologists to become independent Principal Investigators and to play a leading role in combined research and diagnostic careers.
Clinical interests:
Surgical and autopsy neuropathology. Dr. Chu is director of the ophthalmic pathology service. For information on submitting specimens, see http://neuro.pathology.pitt.edu/webstuff/Eye Consults.html. For information on training in academic neuropathology or ophthalmic pathology, see the Neuropathology website. http://neuro.pathology.pitt.edu/
Selected Publications:
(See Dr. Chu's CV for a more complete list and downloads)
View Dr. Chu's recent publications on PubMed
View Dr. Chu's previous publications on PubMed
JH Zhu, C Horbinski, F Guo, S Watkins, Y Uchiyama & CT Chu (2007). Regulation of autophagy by extracellular signal regulated protein kinases during 1-methyl-4-phenylpyridinium injury. Am J. Pathol, 170: 75-86.
EM Chalovich, JH Zhu, J Caltagarone, R Bowser & CT Chu (2006) Functional repression of cAMP response element in 6-hydroxydopamine-treated neuronal cells. J. Biol. Chem, 281: 17870-17881.
CT Chu. (2006) Autophagic stress in neuronal injury and disease. J Neuropath Exp Neurol, 65: 423-432.
CT Chu, JH Zhu, G Cao, A Signore, S Wang & J Chen (2005) Apoptosis-inducing factor mediates caspase-independent 1-methyl-4-phenylpyridinium toxicity in dopaminergic cells. J. Neurochem, 94: 1685-1695.
J Callio, TD Oury & CT Chu (2005) Manganese superoxide dismutase protects against 6-hydroxydopamine injury in mouse brains J Biol Chem, 280:18536-18542.
C Horbinski & CT Chu (2005) Kinase signaling cascades in the mitochondrion: A matter of life or death Free Rad Biol Med. 38: 2-11.
CT Chu, DJ Levinthal, SM Kulich, EM Chalovich, and DB DeFranco (2004) Oxidative neuronal injury: The dark side of ERK 1/2. (peer-reviewed review) Eur J Biochem, 271: 2060-2066 (Cover Article)
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